Solid compositions comprising a glp-1 agonist and a salt of n-(8-(2-hydroxybenzoyl)amino)caprylic acid

ABSTRACT

The present invention relates to solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and their use in medicine.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.17/180,370, filed Feb. 19, 2021, which is a continuation of U.S.application Ser. No. 16/118,381, filed Aug. 30, 2018 (Issued as10,960,052), which is a continuation of U.S. application Ser. No.15/019,412, filed Feb. 9, 2016 (Issued as 10,086,047), which is acontinuation of U.S. application Ser. No. 13/994,262 filed Sep. 16, 2013(Issued as 9,278,123), which is a 35 U.S.C. § 371 National Stageapplication of International Application PCT/EP2011/073060 (WO2012/080471), filed Dec. 16, 2011, which claimed priority of EuropeanPatent Application 10195285.1, filed Dec. 16, 2010; this applicationclaims priority under 35 U.S.C. § 119 of U.S. Provisional Application61/425,087; filed Dec. 20, 2010; the contents of which are incorporatedherein by reference.

INCORPORATION-BY-REFERENCE OF THE SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted in ASCII format via EFS-Web and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Jun. 1, 2022, isnamed 8253US10_SequenceListing_ST25.txt and is 2 kilobytes in size.

FIELD OF THE INVENTION

The present invention relates to solid compositions comprising a GLP-1agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid andtheir use in medicine.

BACKGROUND OF THE INVENTION

Human GLP-1 and analogues thereof have a low oral bioavailability.Exposure and bioavailability of human GLP-1 and analogues thereof isvery low following oral administration. Human GLP-1 and analoguesthereof can only be detected in plasma after oral administration ifformulated with certain absorption enhancers in a specific amount.Steinert et al. (Am 3 Clin Nutr, October 2010; 92: 810-817) disclosesoral administration of a tablet comprising GLP-1(7-36)amide and 150 mgsodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC). WO 2010/020978discloses an oral pharmaceutical composition comprising a protein andN-(8-[2-hydroxybenzoyl) amino)caprylate (SNAC).

There is still a need for an optimized pharmaceutical composition fororal administration of a GLP-1 agonist such as a GLP-1 agonistcomprising a substituent.

SUMMARY OF THE INVENTION

In some embodiments the invention relates to a solid composition fororal administration comprising a GLP-1 agonist and a salt ofN-(8-(2-hydroxybenzoyl)amino) caprylic acid, wherein a) the amount ofsaid salt of N-(8-(2-hydroxybenzoyl)amino) caprylic acid is at least 0.6mmol or at least 0.8 mmol; and b) said GLP-1 agonist is GLP-1 (7-37),GLP-1 (7-36)amide, exendin-4 or an analogue thereof, and wherein saidGLP-1 agonist optionally comprises one substituent. In some embodimentsthe invention relates to the use of a composition as defined herein inmedicine.

DESCRIPTION OF THE INVENTION

The present invention relates to solid compositions of a GLP-1 agonistand salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. Surprisingly,the present inventors have found that solid compositions comprisingcertain amounts of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid,such as SNAC, are optimal for oral administration of GLP-1 agonists.Accordingly, the compositions provide improved exposure and/orbioavailability of the GLP-1 agonist.

Generally, the term “bioavailability” as used herein refers to thefraction of an administered dose of an active pharmaceutical ingredient(API), such as a GLP-1 agonist as defined herein, which reaches thesystemic circulation unchanged. By definition, when an API isadministered intravenously, its bioavailability is 100%. However, whenit is administered via other routes (such as orally), itsbioavailability decreases (due to incomplete absorption and first-passmetabolism). Knowledge about bioavailability is important whencalculating dosages for non-intravenous routes of administration.

Absolute oral bioavailability is calculated as the relative exposure ofthe API in systemic circulation following oral administration (estimatedas the area under the plasma concentration versus time curve, or AUC)compared to the exposure of the API following intravenousadministration.

GLP-1 Agonist

The term “GLP-1 agonist” as used herein refers to a compound, whichfully or partially activates the human GLP-1 receptor. In someembodiments the “GLP-1 agonist” binds to a GLP-1 receptor, e.g., with anaffinity constant (K_(D)) or activate the receptor with a potency (EC₅₀)of below 1 μM, e.g. below 100 nM as measured by methods known in the art(see e.g. WO 98/08871) and exhibits insulinotropic activity, whereinsulinotropic activity may be measured in vivo or in vitro assays knownto those of ordinary skill in the art. For example, the GLP-1 agonistmay be administered to an animal with increased blood glucose (e.g.obtained using an Intravenous Glucose Tolerance Test (IVGTT), a personskilled in the art will be able to determine a suitable glucose dosageand a suitable blood sampling regime, e.g. depending on the species ofthe animal, for the IVGTT) and the plasma insulin concentration measuredover time.

In some embodiments the GLP-1 agonist is a GLP-1 analogue, optionallycomprising one substituent. The term “analogue” as used herein referringto a GLP-1 peptide (hereafter “peptide”) means a peptide wherein atleast one amino acid residue of the peptide has been substituted withanother amino acid residue and/or wherein at least one amino acidresidue has been deleted from the peptide and/or wherein at least oneamino acid residue has been added to the peptide and/or wherein at leastone amino acid residue of the peptide has been modified. Such additionor deletion of amino acid residues may take place at the N-terminal ofthe peptide and/or at the C-terminal of the peptide. In some embodimentsa simple nomenclature is used to describe the GLP-1 agonist, e.g.,[Aib8] GLP-1(7-37) designates an analogue of GLP-1(7-37) wherein thenaturally occurring Ala in position 8 has been substituted with Aib. Insome embodiments the GLP-1 agonist comprises a maximum of twelve, suchas a maximum of 10, 8 or 6, amino acids which have been alterered, e.g.,by substitution, deletion, insertion and/or modification, compared toe.g. GLP-1(7-37). In some embodiments the analogue comprises up to 10substitutions, deletions, additions and/or insertions, such as up to 9substitutions, deletions, additions and/or insertions, up to 8substitutions, deletions, additions and/or insertions, up to 7substitutions, deletions, additions and/or insertions, up to 6substitutions, deletions, additions and/or insertions, up to 5substitutions, deletions, additions and/or insertions, up to 4substitutions, deletions, additions and/or insertions or up to 3substitutions, deletions, additions and/or insertions, compared to e.g.GLP-1(7-37). Unless otherwise stated the GLP-1 comprises only L-aminoacids.

In some embodiments the term “GLP-1 analogue” or “analogue of GLP-1” asused herein refers to a peptide, or a compound, which is a variant ofthe human Glucagon-Like Peptide-1 (GLP-1(7-37)). GLP-1(7-37) has thesequence HAEGTFTSDV SSYLEGQAAKEFIAWLVKGRG (SEQ ID No: 1). In someembodiments the term “variant” refers to a compound which comprises oneor more amino acid substitutions, deletions, additions and/orinsertions.

In one embodiment the GLP-1 agonist exhibits at least 60%, 65%, 70%, 80%or 90% sequence identity to GLP-1(7-37) over the entire length ofGLP-1(7-37). As an example of a method for determination of sequenceidentity between two analogues the two peptides [Aib8]GLP-1(7-37) andGLP-1(7-37) are aligned. The sequence identity of [Aib8]GLP-1(7-37)relative to GLP-1(7-37) is given by the number of aligned identicalresidues minus the number of different residues divided by the totalnumber of residues in GLP-1(7-37). Accordingly, in said example thesequence identity is (31-1)/31.

In one embodiment the C-terminal of the GLP-1 agonist is an amide.

In some embodiments the GLP-1 agonist is GLP-1(7-37) orGLP-1(7-36)amide. In some embodiments the GLP-1 agonist is exendin-4,the sequence of which is HGEGTFITSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQID No: 2).

In some embodiments the GLP-1 agonist comprises one substituent which iscovalently attached to the peptide. In some embodiments the substituentcomprises a fatty acid or a fatty diacid. In some embodiments thesubstituent comprises a C16, C18 or C20 fatty acid. In some embodimentsthe substituent comprises a C16, C18 or C20 fatty diacid. In someembodiments the substituent comprises formula (X)

wherein n is at least 13, such as n is 13, 14, 15, 16, 17, 18 or 19. Insome embodiments the substituent comprises formula (X), wherein n is inthe range of 13 to 19, such as in the range of 13 to 17. In someembodiments the substituent comprises formula (X), wherein n is 13, 15or 17. In some embodiments the substituent comprises formula (X),wherein n is 13. In some embodiments the substituent comprises formula(X), wherein n is 15. In some embodiments the substituent comprisesformula (X), wherein n is 17. In some embodiments the substituentcomprises one or more 8-amino-3,6-dioxaoctanoic acid (OEG), such as twoOEG.

In some embodiments the substituent is[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino] ethoxy}ethoxy)acetyl].

In some embodiments the substituent is[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl].

In some embodiments the GLP-1 agonist is semaglutide, also known asN-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37),which may be prepared as described in WO2006/097537, Example 4.

In some embodiments the composition comprises the GLP-1 agonist or apharmaceutically acceptable salt, amide, or ester thereof. In someembodiments the composition comprises the GLP-1 agonist one or morepharmaceutically acceptable counter ions.

In some embodiments the dosage of GLP-1 is in the range of 0.01 mg to100 mg. In some embodiments the composition comprises an amount of aGLP-1 agonist in the range of 0.1 to 40 mg or 1 to 20 mg. In someembodiments the composition comprises an amount of a GLP-1 agonist inthe range of 5 to 20 mg, such as in the range of 5 to 15 mg, such as 5mg, such as 10 mg, such as 15 mg, such as 20 mg.

In some embodiments the composition comprises an amount of a GLP-1agonist in the range of 0.05 to 25 μmol, such as in the range of 0.5 to2.5 μmol.

In some embodiments the GLP-1 agonist is selected from one or more ofthe GLP-1 agonists mentioned in WO93/19175, WO96/29342, WO98/08871,WO99/43707, WO99/43706, WO99/43341, WO99/43708, WO2005/027978,WO2005/058954, WO2005/058958, WO2006/005667, WO2006/037810,WO2006/037811, WO2006/097537, WO2006/097538, WO2008/023050,WO2009/030738, WO2009/030771 and WO2009/030774.

In some embodiments the GLP-1 agonist is selected from the groupconsisting ofN-epsilon37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)amide;N-epsilon26{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl [desaminoHis7, Arg34] GLP-1-(7-37);N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-carboxyheptadecanoyl)piperidin-4-ylcarbonylamino]3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][,DesaminoHis7,Glu22 Arg26, Arg 34, Phe(m-CF3)28]GLP-1-(7-37)amide;N-epsilon26-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyryl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-{4-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]butyryl}[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(trans-19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon26[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy) acetylamino]ethoxy}ethoxy)acetyl[Aib8, Lys 26]GLP-1(7-37)amide; N-epsilon26[2-(2-[2-(2-[2-(2-((S)-2-[trans-4-((9-carboxynonadecanoylamino] methyl)cyclohexylcarbonylamino]-4-carboxybutanoylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8, Lys26] GLP-1 (7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexane-carbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazol-5-yl)-hexadecanoylsulfamoyl)butyrylamino]-butyrylamino}butyrylamino)butyrylamino] ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]butyrylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]-dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-36)amide;N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyryl-amino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Lys33,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Ab8,Arg34]GLP-1-(7-36)amide;N-epsilon26-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[(S)4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino) butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Lys26,Arg34]GLP-1-(7-36)amide;N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy] ethoxy}acetyl[desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)amide;N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy] ethoxy} acetyl [Aib8,Glu22,Arg26,Arg34, Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-carboxyhepta-decanoyl)piperidin-4-ylcarbonylamino]3-carboxy-propionylamino)ethoxy)ethoxy] acetylamino) ethoxy] ethoxy)acetyl] [DesaminoHis7,Glu22,Arg26, Arg34,Phe(m-CF3)28] GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy} ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy} ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino] ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino} butyrylamino) butyrylamino]ethoxy}ethoxy)acetyl] [Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-(3-((2-(2-(2-(2-(2-Hexadecyloxyethoxy)ethoxy)ethoxy) ethoxy)ethoxy))propionyl)[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxybutyryl-amino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-[desaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37] GLP-1-(7-37)amide;N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxybutyryl-amino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy) acetyl)}-[desaminoHis7,Glu22, Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-(2-(2-(2-(2-(2-(2-(2-(2-(2-(octadecanoyl-amino)ethoxy)ethoxy)acetylamino)ethoxy) ethoxy)acetylamino) ethoxy)ethoxy)acetyl)[desaminoHis7,Glu22,Arg26,Arg34,Lys37] GLP-1 (7-37)amide;N-epsilon37-[4-(16-(1H-Tetrazol-5-yl)hexadecanoylsulfamoyl) butyryl][DesaminoHis7,Glu22,Arg26, Arg34, Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(19-carboxynonadecanoylamino)butyrylamino] ethoxy}ethoxy) acetylamino]ethoxy} ethoxy)acetyl][DesaminoHis7,Glu22,Arg26, Arg34,Lys37]GLP-1-(7-37);N-epsilon37-(2-{2-[2-((S)-4-carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyrylamino]butyrylamino}butyrylamino)ethoxy]ethoxy}acetyl)[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-{2-[2-(2-{(S)-4-[(S)-4-(12-{4-[16-(2-tert-Butyl-2H-tetrazol-5-yl)-hexadecanoylsulfamoyl]butyrylamino}dodecanoylamino)-4-carboxybutyrylamino]-4-carboxybutyrylamino}ethoxy)ethoxy]acetyl}[DesaminoHis7,Glu22,Arg26,Arg34,Lys37] GLP-1(7-37);N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][Aib8,Glu22, Arg26,Arg34,Lys37]GLP-1-(7-37);N-alpha37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][Aib8,Glu22,Arg26,Arg34,epsilon-Lys37]GLP-1-(7-37)peptide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][desaminoHis7, Glu22,Arg26,Arg34,Lys37] GLP-1-(7-37);N-epsilon36-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxy-pentadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)acetylamino]-ethoxy}-ethoxy)-acetyl][desaminoHis7, Glu22,Arg26,Glu30,Arg34,Lys36]GLP-1-(7-37)-Glu-Lyspeptide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Ab8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)acetyl]-[Aib8,Glu22,Arg26,Arg34,Aib35,Lys37]GLP-1-(7-37);N-epsilon37-[(S)-4-carboxy-4-(2-{2-[2-(2-{2-[2-(17-carboxyheptadecanoylamino)ethoxy] ethoxy} acetylamino) ethoxy] ethoxy} acetylamino) butyryl][Aib8,Glu22,Arg26,34,Lys37] GLP-1 (7-37);N-epsilon37-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][ImPr7,Glu22, Arg26,34,Lys37], GLP-1-(7-37);N-epsilon26-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy] acetylamino}ethoxy)ethoxy]acetyl},N-epsilon37-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino] butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl}-[Aib8,Arg34,Lys37]GLP-1(7-37)-OH; N-epsilon26(17-carboxyheptadecanoyl)-[Aib8,Arg34]GLP-1-(7-37)-peptide;N-epsilon26-(19-carboxynonadecanoyl)[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-(4-{[N-(2-carboxyethyl)-N-(15-carboxypentadecanoyl)amino]methyl}benzoyl[Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino) ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(19-carboxynonadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][3-(4-Imidazolyl)Propionyl7,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-(carboxymethylamino)acetylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-3(S)Sulfopropionylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Ab8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37)-amide;N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34,Pro37]GLP-1-(7-37)amide;Aib8,Lys26(N-epsilon26-{2-(2-(2-(2-[2-(2-(4-(pentadecanoylamino)-4-carboxybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}), Arg34)GLP-1 H(7-37)-OH;N-epsilon26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxyheptadecanoyl)amino]methyl}benzoyl)amino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37);N-alpha7-formyl,N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoyl-amino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Arg34]GLP-1-(7-37);N-epsilon2626-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Glu22, Arg34]GLP-1-(7-37);N-epsilon26{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(15-(N-((S)-1,3-dicarboxypropyl)carbamoyl)pentadecanoylamino)-(S)-4-carboxybutyrylamino] ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl}[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxyheptadecanoyl)amino]methyl}benzoyl)amino](4(S)-carboxybutyryl-amino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34] GLP-1(7-37);N-epsilon26-{(S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-(19-carboxynonadecanoylamino)butyrylamino)butyrylamino)butyrylamino)butyrylamino}[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-4-(17-carboxyheptadecanoyl-amino)-4(S)carboxybutyryl-[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl}[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-{2-(2-(2-(2-[2-(2-(4-(17-carboxyheptadecanoylamino)-4-carboxybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-[Aib8,22,27,30,35,Arg34,Pro37,Lys26] GLP-1 (7-37)amide;N-epsilon26-[2-(2-[2-[4-(21-carboxyuneicosanoylamino)-4(S)carboxybutyrylamino]ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);andN-epsilon26-[2-(2-[2-(2-[2-(2-[4-(21-carboxyuneicosanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37).

Delivery Agent: salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid

The delivery agent used in the present invention is a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid. The structural formula ofN-(8-(2-hydroxybenzoyl)amino)caprylate is shown in formula (I).

In some embodiments the salt of N-(8-(2-hydroxybenzoyl)amino)caprylicacid comprises one monovalent cation, two monovalent cations or onedivalent cation. In some embodiments the salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid is selected from the groupconsisting of the sodium salt, potassium salt and calcium salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid.

Salts of N-(8-(2-hydroxybenzoyl)amino)caprylate may be prepared usingthe method described in e.g. WO96/030036, WO0/046182, WO01/092206 orWO2008/028859.

The salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may becrystalline and/or amorphous. In some embodiments the delivery agentcomprises the anhydrate, monohydrate, dihydrate, trihydrate, a solvateor one third of a hydrate of the salt of N(8-(2-hydroxybenzoyl)amino)caprylic acid as well as combinations thereof. In some embodiments thedelivery agent is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acidas described in WO2007/121318.

In some embodiments the delivery agent is sodiumN-(8-(2-hydroxybenzoyl)amino)caprylate (referred to as “SNAC” herein),also known as sodium 8-(salicyloylamino) octanoate.

In some embodiments the amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid in the composition is at least 0.6 mmol, such asselected from the group consisting of at least 0.65 mmol, at least 0.7mmol, at least 0.75 mmol, at least 0.8 mmol, at least 0.8 mmol, at least0.9 mmol, at least 0.95 mmol and at least 1 mmol. In some embodimentsthe amount of the salt of N-(8-(2-hydroxybenzoyl) amino)caprylic acid inthe composition is in the range of 0.6-2.1 mmol or 0.6-1.9 mmol. In someembodiments the amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid in the composition is in the range of 0.7-1.7 mmolor 0.8-1.3 mmol. In some embodiments the amount of the salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid in the composition is up to2.1 mmol, such as selected from the group consisting of up to 2.1 mmol,up to 2 mmol, up to 1.9 mmol, up to 1.8 mmol, up to 1.7 mmol, up to 1.6mmol, up to 1.5 mmol, up to 1.4 mmol, up to 1.3 mmol, up to 1.2 mmol andup to 1.1 mmol. In some embodiments the amount of the salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid is 1 mmol, such as 1.08 mmol.

In some embodiments the amount of SNAC in the composition is at least175 mg, such as an amount selected from the group consisting of at least200 mg, at least 210 mg, at least 220 mg, at least 230 mg, at least 240mg, at least 250 mg, at least 260 mg, at least 270 mg and at least 280mg. In some embodiments the amount of SNAC in the composition is in therange of 175-575 mg, such as 200-500 mg or 250-400 mg. In someembodiments the amount of SNAC in the composition is up to 575 mg, suchas an amount selected from the group consisting of up to 550 mg, up to525 mg, up to 500 mg, up to 475 mg, up to 450 mg, up to 425 mg, up to400 mg, up to 375 mg, up to 350 mg and up to 325 mg. In some embodimentsthe amount of SNAC in the composition is 300 mg.

In some embodiments the molar ratio between GLP-1 agonist and deliveryagent in the composition is less than 10, such as less than 5 or lessthan 1.

Composition

The composition of the present invention is a solid composition and isadministered by the oral route.

In some embodiments the composition comprises at least onepharmaceutically acceptable excipient. The term “excipient” as usedherein broadly refers to any component other than the active therapeuticingredient(s). The excipient may be an inert substance, an inactivesubstance, and/or a not medicinally active substance. The excipient mayserve various purposes, e.g. as a carrier, vehicle, filler, binder,lubricant, glidant, disintegrant, flow control agents, crystallizationretarders, solubilizers, stabilizer, colouring agent, flavouring agent,surfactant, emulsifier and/or to improve administration, and/orabsorption of the active substance. A person skilled in the art mayselect one or more of the aforementioned excipients with respect to theparticular desired properties of the solid oral dosage form by routineexperimentation and without any undue burden. The amount of eachexcipient used may vary within ranges conventional in the art.Techniques and excipients which may be used to formulate oral dosageforms are described in Handbook of Pharmaceutical Excipients, 6thedition, Rowe et al., Eds., American Pharmaceuticals Association and thePharmaceutical Press, publications department of the RoyalPharmaceutical Society of Great Britain (2009); and Remington: theScience and Practice of Pharmacy, 21th edition, Gennaro, Ed., LippincottWilliams & Wilkins (2005). In some embodiments the excipients may beselected from binders, such as polyvinyl pyrrolidone (povidone), etc.;fillers such as cellulose powder, microcrystalline cellulose, cellulosederivatives like hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and hydroxy-propylmethylcellulose, dibasiccalcium phosphate, corn starch, pregelatinized starch, etc.; lubricantsand/or glidants such as stearic acid, magnesium stearate, sodiumstearylfumarate, glycerol tribehenate, etc.; flow control agents such ascolloidal silica, talc, etc.; crystallization retarders such asPovidone, etc.; solubilizers such as Pluronic, Povidone, etc.; colouringagents, including dyes and pigments such as Iron Oxide Red or Yellow,titanium dioxide, talc, etc.; pH control agents such as citric acid,tartaric acid, fumaric acid, sodium citrate, dibasic calcium phosphate,dibasic sodium phosphate, etc.; surfactants and emulsifiers such asPluronic, polyethylene glycols, sodium carboxymethyl cellulose,polyethoxylated and hydrogenated castor oil, etc.; and mixtures of twoor more of these excipients and/or adjuvants.

In some embodiments the composition comprises at least 60% (w/w)delivery agent, less than 10% (w/w) binder, 5-40% (w/w) filler, and lessthan 10% (w/w) lubricant or glidant.

In some embodiments the composition comprises at least 60% (w/w), suchas at least 70% (w/w) or at least 75% (w/w), delivery agent.

In some embodiments the composition comprises 0.1-10% (w/w), such as0.2-4% (w/w) or 0.5-3% (w/w), of binder. In some embodiments thecomposition comprises 1% (w/w) or 2% (w/w) of binder. The compositionmay comprise a binder, such as povidone; starches; celluloses andderivatives thereof, such as microcrystalline cellulose, e.g., AVICEL PHfrom FMC (Philadelphia, Pa.), hydroxypropyl cellulose hydroxylethylcellulose and hydroxylpropylmethyl cellulose METHOCEL from Dow ChemicalCorp. (Midland, Mich.); sucrose; dextrose; corn syrup; polysaccharides;and gelatin. The binder may be selected from the group consisting of drybinders and/or wet granulation binders. Suitable dry binders are, e.g.,cellulose powder and microcrystalline cellulose, such as Avicel PH 102and Avicel PH 200. In some embodiments the composition comprises avicel,such as avicel PH 102. Suitable binders for wet granulation or drygranulation are corn starch, polyvinyl pyrrolidone (povidon),vinylpyrrolidone-vinylacetate copolymer (copovidone) and cellulosederivatives like hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and hydroxyl-propylmethylcellulose. In someembodiments the composition comprises povidone.

In some embodiments the composition comprises 5-40% (w/w), such as10-30% (w/w) or 5-25% (w/w), of filler. In some embodiments thecomposition comprises 10.9% (w/w) or 18% (w/w) of filler, or comprises19.5% (w/w) or 20.5 (w/w) of filler. The filler may be selected fromlactose, mannitol, erythritol, sucrose, sorbitol, calcium phosphate,such as calciumhydrogen phosphate, microcrystalline cellulose, powderedcellulose, confectioner's sugar, compressible sugar, dextrates, dextrinand dextrose. In some embodiments the composition comprisesmicrocrystalline cellulose, such as Avicel PH 102 or Avicel PH 200.

In some embodiments the composition comprises 0.1-10% (w/w) or 0.5-5%(w/w), such as 1-3.5% (w/w) or 1% (w/w), of lubricant and/or a glidant.In some embodiments the composition comprises a lubricant and/or aglidant, such as talc, magnesium stearate, calcium stearate, zincstearate, glyceryl behenate, polyethylene oxide polymers, sodium laurylsulfate, magnesium lauryl sulfate, sodium oleate, sodium stearylfumarate, stearic acid, hydrogenated vegetable oils, silicon dioxideand/or polyethylene glycol. In some embodiments the compositioncomprises magnesium stearate.

In some embodiments the composition comprises a disintegrant, such assodium starch glycolate, polacrilin potassium, sodium starch glycolate,crospovidon, croscarmellose, sodium carboxymethylcellulose or dried cornstarch.

The composition may comprise one or more surfactants, for example asurfactant, at least one surfactant, or two different surfactants. Theterm “surfactant” refers to any molecules or ions that are comprised ofa water-soluble (hydrophilic) part, and a fatsoluble (lipophilic) part.The surfactant may e.g. be selected from the group consisting of anionicsurfactants, cationic surfactants, nonionic surfactants, and/orzwitterionic surfactants.

Still further, the composition may be formulated as is known in the artof oral formulations of insulinotropic compounds, e.g. using any one ormore of the formulations described in WO 2008/145728.

A composition may also be used in the formulation of site specific,controlled, sustained, protracted, prolonged, delayed, pulsatile,retarded, and/or slow release drug delivery systems.

The composition of the invention may be prepared as is known in the art.

The composition may be administered in several dosage forms, for exampleas a tablet; a coated tablet; a chewing gum; a capsule such as hard orsoft gelatine capsules or a powder. The composition may further becompounded in a drug carrier or drug delivery system, e.g. in order toimprove stability and/or solubility or further improve bioavailability.The composition may be a freeze-dried or spray-dried composition.

The composition may be in the form of a tablet. In some embodiments theweight of the tablet is in the range of 175 mg to 1000 mg, such as inthe range of 175-250 mg, 300-500 mg or 500-900 mg, or such as about 200mg, about 400 mg or about 700 mg. In some embodiments the weight of thetablet is in the range of 200 mg to 1000 mg, such as in the range of500-700 mg or 600-1000 mg, or such as about 200 mg, about 400 mg, about600 mg or about 800 mg.

In some embodiments the composition may be granulated prior to beingcompacted. The composition may comprise an intragranular part and anextragranular part, wherein the intragranular part has been granulatedand the extragranular part has been added after granulation. Theintragranular part may comprise the GLP-1 agonist, the delivery agentand a binder. In some embodiments the intragranular part comprisespovidone. The extragranular part may comprise a filler, a lubricantand/or a glidant. In some embodiments the extragranular part comprisesmicrocrystalline cellulose, such as avicel, e.g. avicel PH120 or avicelPH200. In some embodiments the extragranular part comprises magnesiumstearate.

To prepare a dry blend of tabletting material, the various componentsare weighed, optionally delumped and then combined. The mixing of thecomponents may be carried out until a homogeneous blend is obtained.

If granules are to be used in the tabletting material, granules may beproduced in a manner known to a person skilled in the art, for exampleusing wet granulation methods known for the production of “built-up”granules or “broken-down” granules. Methods for the formation ofbuilt-up granules may operate continuously and comprise, for examplesimultaneously spraying the granulation mass with granulation solutionand drying, for example in a drum granulator, in pan granulators, ondisc granulators, in a fluidized bed, by spray-drying orspray-solidifying, or operate discontinuously, for example in afluidized bed, in a rotary fluid bed, in a batch mixer, such as a highshear mixer or a low shear mixer, or in a spray-drying drum. Methods forthe production of broken-down granules, which may be carried outdiscontinuously and in which the granulation mass first forms a wetaggregate with the granulation solution, which is subsequentlycomminuted or by other means formed into granules of the desired sizeand the granules may then be dried. Suitable equipment for thegranulation step are planetary mixers, low shear mixers, high shearmixers, extruders and spheronizers, such as an apparatus from thecompanies Loedige, Glatt, Diosna, Fielder, Collette, Aeschbach,Alexanderwerk, Ytron, Wyss & Probst, Werner & Pfleiderer, HKD, Loser,Fuji, Nica, Caleva and Gabler. Granules may be also formed by drygranulation techniques in which the pharmaceutically active agent iscompressed with the excipients to form relatively large moldings, forexample slugs or ribbons, which are comminuted by grinding, and theground material serves as the tabletting material to be later compacted.Suitable equipment for dry granulation is roller compaction equipmentfrom Gerteis, such as Gerteis MINI-PACTOR.

To compact the tabletting material into a solid oral dosage form, forexample a tablet, a tablet press may be used. In a tabletting press, thetabletting material is filled (e.g. force fed or gravity fed) into a diecavity. The tabletting material is then compacted by a punch withpressure. Subsequently, the resulting compact, or tablet is ejected fromthe tabletting press. The above mentioned compaction process issubsequently referred to herein as the “compaction process”. Suitabletablet presses include, but are not limited to, rotary tablet pressesand eccentric tablet presses. Examples of tablet presses include, butare not limited to, the Fette 102i (Fette GmbH), the Korsch XL100, theKorsch PH 106 rotary tablet press (Korsch AG, Germany), the Korsch EK-Oeccentric tabletting press (Korsch AG, Germany) and the Manesty F-Press(Manesty Machines Ltd., United Kingdom).

In some embodiments the method of preparation of the tablet comprises a)wet granulation of a mixture comprising the GLP-1 agonist, the deliveryagent and a binder; b) optionally drying the wet granulate; c) blendingof the dried wet granulates with at least a filler and at least alubricant or a glidant, and then d) compression of the blend intotablets. The granulation may be a wet granulation or a dry granulation.

Disintegration Time:

In some embodiments the disintegration time of the tablet is in therange of 7 minutes to 15 minutes, such as in the range of 8 minutes to13 minutes. Disintegration time may be determined using a Pharma TestPTZ AUTO disintegration test apparatus. The disintegration apparatusconsists of a basket rack holding 2×6 plastic tubes, open at the top andbottom, the bottom of the tube is covered by a screen. Tablets areplaced in the tubes and on top of the tablets are placed discs forautomated disintegration detection. The basket is immersed in 800 mlpurified water maintained at 37° C., in a 1 L beaker. Time for completedisintegration is measured. Furthermore, tablets may be observedvisually for surface eroding behaviour during the disintegration test.

In some embodiments the tablet of the invention co-releases the activeingredients and the delivery agent by surface erosion; hence, thetablets becomes smaller and smaller with time by dissolution primarilyfrom the surface from non-disintegrated tablets. Concurrent release: Insome embodiments the compositions show concurrent release of the GLP-1agonist and the delivery agent from the surface of the tablet. This canbe tested by visual inspection during the disintegration test; thetablets do not have concurrent release of the GLP-1 agonist and thedelivery agent from the surface of the tablet if the tablet breaks intosmaller parts during the first 8 minutes of the disintegration test.

Dissolution Test:

Another test for concurrent release of the GLP-1 agonist and thedelivery agent is the dissolution test. Here, the rate of appearance (inpercentage) of the GLP-1 agonist and the delivery agent is measured. Thedissolution test may be carried out as described in the following:Dissolution is performed on a Varian 705 DS. The analysis is based onthe pharmacopeia method Ph Eur 2.9.3, Apparatus 2 (Paddle apparatus).100 ml mini vessel with mini-paddles is used, and paddle speed is 75rpm. After 120 minutes, the paddle speed is changed to 250 rpm. Thedissolution medium used for the dissolution test is 100 ml of 200 mMKH2PO4 (containing 0.07% Tween 80 to avoid the GLP-1 agonist fromsticking to the wall of the bath and to the paddle), with pH 6.8.Samples are taken after 5, 15, 30, 45, 60, 120 and 135 minutes. Thevolume of the sample is 2 ml, and the sample is taken with a disposablesyringe. After each sample is taken, the same volume (2 ml) of thedissolution medium is added to the bath, in order to keep the totalvolume of 100 ml constant. The sample is pressed through a 0.22 pmMillex®-GV filter. Finally, the samples are analysed for concentrationof the GLP-1 agonist and for concentration of the delivery agent byUPLC.

Hardness Test:

The hardness of the tablets is measured with a Pharma Test (33AA02),which measures the force required to disrupt the tablet, and the test isbased on the pharmacopeia method Ph Eur 2.9.8.

The treatment with a composition according to the present invention mayalso be combined with one or more additional pharmacologically activesubstances, e.g. selected from antidiabetic agents, antiobesity agents,appetite regulating agents, antihypertensive agents, agents for thetreatment and/or prevention of complications resulting from orassociated with diabetes and agents for the treatment and/or preventionof complications and disorders resulting from or associated withobesity. Examples of these pharmacologically active substances are:Insulin, sulphonylureas, biguanides, meglitinides, glucosidaseinhibitors, glucagon antagonists, DPP-IV (dipeptidyl peptidase-IV)inhibitors, inhibitors of hepatic enzymes involved in stimulation ofgluconeogenesis and/or glycogenolysis, glucose uptake modulators,compounds modifying the lipid metabolism such as antihyperlipidemicagents as HMG CoA inhibitors (statins), Gastric Inhibitory Polypeptides(GIP analogs), compounds lowering food intake, RXR agonists and agentsacting on the ATP-dependent potassium channel of the p-cells;Cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin,pravastatin, simvastatin, probucol, dextrothyroxine, neteglinide,repaglinide; p-blockers such as alprenolol, atenolol, timolol, pindolol,propranolol and metoprolol, ACE (angiotensin converting enzyme)inhibitors such as benazepril, captopril, enalapril, fosinopril,lisinopril, alatriopril, quinapril and ramipril, calcium channelblockers such as nifedipine, felodipine, nicardipine, isradipine,nimodipine, diltiazem and verapamil, and α-blockers such as doxazosin,urapidil, prazosin and terazosin; CART (cocaine amphetamine regulatedtranscript) agonists, NPY (neuropeptide Y) antagonists, PYY agonists, Y2receptor agonists, Y4 receptor agonits, mixed Y2/Y4 receptor agonists,MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosisfactor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP(corticotropin releasing factor binding protein) antagonists, urocortinagonists, β3 agonists, oxyntomodulin and analogues, MSH(melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentratinghormone) antagonists, CCK (cholecystokinin) agonists, serotoninre-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors,mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists,bombesin agonists, galanin antagonists, growth hormone, growth hormonereleasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DAagonists (bromocriptin, doprexin), lipase/amylase inhibitors, RXR(retinoid X receptor) modulators, TR β agonists; histamine H3antagonists, Gastric Inhibitory Polypeptide agonists or antagonists (GIPanalogs), gastrin and gastrin analogs.

Additional embodiments of the compositions of the invention aredescribed in the section headed “particular embodiments” before theexperimental section.

Pharmaceutical Indications

The present invention also relates to a composition of the invention foruse as a medicament. In particular embodiments the composition of theinvention may be used for the following medical treatments, allpreferably relating one way or the other to diabetes:

(i) prevention and/or treatment of all forms of diabetes, such ashyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1diabetes, non-insulin dependent diabetes, MODY (maturity onset diabetesof the young), gestational diabetes, and/or for reduction of HbA1C;

(ii) delaying or preventing diabetic disease progression, such asprogression in type 2 diabetes, delaying the progression of impairedglucose tolerance (IGT) to insulin requiring type 2 diabetes, and/ordelaying the progression of non-insulin requiring type 2 diabetes toinsulin requiring type 2 diabetes;

(iii) improving β-cell function, such as decreasing β-cell apoptosis,increasing Pcell function and/or β-cell mass, and/or for restoringglucose sensitivity to β-cells;

(iv) prevention and/or treatment of cognitive disorders;

(v) prevention and/or treatment of eating disorders, such as obesity,e.g. by decreasing food intake, reducing body weight, suppressingappetite, inducing satiety; treating or preventing binge eatingdisorder, bulimia nervosa, and/or obesity induced by administration ofan antipsychotic or a steroid; reduction of gastric motility; and/ordelaying gastric emptying;

(vi) prevention and/or treatment of diabetic complications, such asneuropathy, including peripheral neuropathy; nephropathy; orretinopathy;

(vii) improving lipid parameters, such as prevention and/or treatment ofdyslipidemia, lowering total serum lipids; lowering HDL; lowering small,dense LDL; lowering VLDL: lowering triglycerides; lowering cholesterol;increasing HDL; lowering plasma levels of lipoprotein a (Lp(a)) in ahuman; inhibiting generation of apolipoprotein a (apo(a)) in vitroand/or in vivo;

(iix) prevention and/or treatment of cardiovascular diseases, such assyndrome X; atherosclerosis; myocardial infarction; coronary heartdisease; stroke, cerebral ischemia; an early cardiac or earlycardiovascular disease, such as left ventricular hypertrophy; coronaryartery disease; essential hypertension; acute hypertensive emergency;cardiomyopathy; heart insufficiency; exercise tolerance; chronic heartfailure; arrhythmia; cardiac dysrhythmia; syncopy; atheroschlerosis;mild chronic heart failure; angina pectoris; cardiac bypass reocclusion;intermittent claudication (atheroschlerosis oblitterens); diastolicdysfunction; and/or systolic dysfunction;

(ix) prevention and/or treatment of gastrointestinal diseases, such asinflammatory bowel syndrome; small bowel syndrome, or Crohn's disease;dyspepsia; and/or gastric ulcers;

(x) prevention and/or treatment of critical illness, such as treatmentof a critically ill patient, a critical illness poly-nephropathy (CIPNP)patient, and/or a potential CIPNP patient; prevention of criticalillness or development of CIPNP; prevention, treatment and/or cure ofsystemic inflammatory response syndrome (SIRS) in a patient; and/or forthe prevention or reduction of the likelihood of a patient sufferingfrom bacteraemia, septicaemia, and/or septic shock duringhospitalisation; and/or

(xi) prevention and/or treatment of polycystic ovary syndrome (PCOS).

In a particular embodiment, the indication is selected from the groupconsisting of (i)-(iii) and (v)-(iix), such as indications (i), (ii),and/or (iii); or indication (v), indication (vi), indication (vii),and/or indication (iix). In another particular embodiment, theindication is (i). In a further particular embodiment the indication is(v). In a still further particular embodiment the indication is (iix).In some embodiments the indications are type 2 diabetes and/or obesity.

FURTHER EMBODIMENTS

-   1. A solid composition for oral administration comprising a GLP-1    agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid,    wherein the amount of said salt of    N(8-(2-hydroxybenzoyl)amino)caprylic acid is at least 0.6 mmol.-   2. A solid composition for oral administration comprising a GLP-1    agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid,    wherein the amount of said salt of    N(8-(2-hydroxybenzoyl)amino)caprylic acid is at least 0.8 mmol.

Form of Composition

-   3. A composition according to any one of the preceding embodiments,    wherein said composition is in the form of a tablet.-   4. A composition according to any one of the preceding embodiments,    wherein the tablet has a weight in the range of 175-1000 mg.-   5. A composition according to any one of the preceding embodiments,    wherein the tablet has a weight in the range of 200-800 mg.-   6. A composition according to any one of the preceding embodiments,    wherein the tablet has a weight selected from the group consisting    of 200 mg, such as 400 mg or 700 mg.-   7. A composition according to any one of the preceding embodiments,    wherein the tablet has a weight selected from the group consisting    of 200 mg, 400 mg, 600 mg or 800 mg.    Salt of N-(8-(2-hydroxybenzoyl)amino)caprylic Acid-   8. A composition according to any one of the preceding embodiments,    wherein said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid    comprises one monovalent cation, two monovalent cations or one    divalent cation.-   9. A composition according to any one of the preceding embodiments,    wherein said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is    selected from the group consisting of the sodium salt, potassium    salt and calcium salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.-   10. A composition according to any one of the preceding embodiments,    wherein said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is    sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC).    Amount of Salt of N-(8-(2-hydroxybenzoyl)amino)caprylic Acid-   11. A composition according to any one of the preceding embodiments,    wherein the amount of said salt of    N-(8-(2-hydroxybenzoyl)amino)caprylic acid is in the range of    0.6-2.1 mmol, such as 0.6-1.9 mmol, 0.7-1.7 mmol or 0.8-1.3 mmol.-   12. A composition according to any one of the preceding embodiments,    wherein the amount of said salt of    N-(8-(2-hydroxybenzoyl)amino)caprylic acid is at least 0.6 mmol,    such as selected from the group consisting of at least 0.65 mmol, at    least 0.7 mmol, at least 0.75 mmol, at least 0.8 mmol, at least 0.8    mmol, at least 0.9 mmol, at least 0.95 mmol and at least 1 mmol.-   13. A composition according to any one of the preceding embodiments,    wherein the amount of said salt of    N-(8-(2-hydroxybenzoyl)amino)caprylic acid is up to 2.1 mmol, such    as selected from the group consisting of up to 2.1 mmol, up to 2    mmol, up to 1.9 mmol, up to 1.8 mmol, up to 1.7 mmol, up to 1.6    mmol, up to 1.5 mmol, up to 1.4 mmol, up to 1.3 mmol, up to 1.2 mmol    and up to 1.1 mmol.-   14. A composition according to any one of the preceding embodiments,    wherein the amount of said salt of    N-(8-(2-hydroxybenzoyl)amino)caprylic acid is 1 mmol, such as 1.08    mmol.-   15. A composition according to any one of the preceding embodiments,    wherein said composition comprises at least 60% (w/w), such as at    least 70% (w/w) or at least 75% (w/w), of said salt of    N-(8-(2-hydroxybenzoyl)amino)caprylic acid.

Amount of SNAC

-   16. A composition according to embodiment 10, wherein the amount of    SNAC is at least 175 mg, such as an amount selected from the group    consisting of at least 200 mg, at least 210 mg, at least 220 mg, at    least 230 mg, at least 240 mg, at least 250 mg, at least 260 mg, at    least 270 mg and at least 280 mg.-   17. A composition according to embodiment 10, wherein the amount of    SNAC is up to 575 mg, such as an amount selected from the group    consisting of up to 550 mg, up to 525 mg, up to 500 mg, up to 475    mg, up to 450 mg, up to 425 mg, up to 400 mg, up to 375 mg, up to    350 mg and up to 325 mg.-   18. A composition according to embodiment 10, wherein the amount of    SNAC is 300 mg.

GLP-1

-   19. A composition according to any one of the preceding embodiments,    wherein the amount of the GLP-1 agonist is in the range of 0.01 mg    to 100 mg.-   20. A composition according to any one of the preceding embodiments,    wherein the GLP-1 agonist comprises one substituent.-   21. A composition according to any one of the preceding embodiments,    wherein said substituent comprises a fatty acid or a fatty diacid.-   22. A composition according to any one of the preceding embodiments,    wherein said substituent comprises a C16, C18 or C20 fatty acid.-   23. A composition according to any one of the preceding embodiments,    wherein said substituent comprises a C16, C18 or C20 fatty diacid.-   24. A composition according to any one of the preceding embodiments,    wherein said substituent comprises formula (X)

-   -   wherein n is at least 13, such as n is 13, 14, 15, 16, 17, 18 or        19.

-   25. A composition according to any one of the preceding embodiments,    wherein said substituent comprises one or more    8-amino-3,6-dioxaoctanoic acid (OEG), such as two OEG.

-   26. A composition according to any one of the preceding embodiments,    wherein the GLP-1 agonist is GLP-1 (7-37), GLP-1 (7-36)amide,    exendin-4 or an analogue thereof comprising up to 10 substitutions,    deletions, additions and/or insertions, wherein said GLP-1 agonist    optionally comprises one substituent.

-   27. A composition according to any one of the preceding embodiments,    wherein the GLP-1 agonist is GLP-1 (7-37), GLP-1 (7-36)amide,    exendin-4 or an analogue thereof comprising up to 7 substitutions,    deletions, additions and/or insertions, wherein said GLP-1 agonist    optionally comprises one substituent.

-   28. A composition according to any one of the preceding embodiments,    wherein the GLP-1 agonist is GLP-1 (7-37), GLP-1 (7-36)amide,    exendin-4 or an analogue thereof comprising up to 4 substitutions,    deletions, additions and/or insertions, wherein said GLP-1 agonist    optionally comprises one substituent.

-   29. A composition according to any one of the preceding embodiments,    wherein the GLP-1 agonist is GLP-1 (7-37), GLP-1 (7-36)amide,    exendin-4 or an analogue thereof comprising up to 3 substitutions,    deletions, additions and/or insertions, wherein said GLP-1 agonist    optionally comprises one substituent.

-   30. A composition according to any one of the preceding embodiments,    wherein the GLP-1 agonist is semaglutide.

-   31. A composition according to any one of the preceding embodiments,    wherein the amount of the GLP-1 agonist is in the range of 1 to 20    mg, such as in the range of 5 to 20 mg, such as in the range of 5 to    15 mg, such as 10 mg.

-   32. A composition according to any one of the preceding embodiments,    wherein the amount of GLP-1 is in the range of 0.05 to 25 μmol, such    as in the range of 0.5 to 2.5 μmol.

Further Excipients

-   33. A composition according to any one of the preceding embodiments,    wherein said composition comprises at least one additional    pharmaceutically acceptable excipient.-   34. A composition according to any one of the preceding embodiments,    wherein said excipient is selected from one or more from the group    consisting of binders, fillers, disintegrants and lubricants and/or    glidants.-   35. A composition according to any one of the preceding embodiments,    wherein said composition comprises 0.1-10% (w/w), such as 0.2-4%    (w/w) or 0.5-3% (w/w), of binder.-   36. A composition according to any one of the preceding embodiments,    wherein said composition comprises 1% (w/w) or 2% (w/w) of binder.-   37. A composition according to any one of the preceding embodiments,    wherein said binder is povidone.-   38. A composition according to any one of the preceding embodiments,    wherein said composition comprises 5-40% (w/w), such as 10-30% (w/w)    or 5-25% (w/w), of filler.-   39. A composition according to any one of the preceding embodiments,    wherein said composition comprises 10.9% (w/w) or 18% (w/w) of    filler, or comprises 19.5% (w/w) or 20.5 (w/w) of filler.-   40. A composition according to any one of the preceding embodiments,    wherein said filler is avicel, such as avicel PH 102 or avicel PH    200.-   41. A composition according to any one of the preceding embodiments,    wherein said composition comprises 0.1-10% (w/w) or 0.5-5% (w/w)    lubricant and/or a glidant.-   42. A composition according to any one of the preceding embodiments,    wherein said composition comprises 1-3.5% (w/w) or 1% (w/w)    lubricant and/or a glidant.-   43. A composition according to any one of the preceding embodiments,    wherein said excipient is magnesium stearate.-   44. A composition according to any one of the preceding embodiments,    wherein said composition comprises at least 60% (w/w) delivery    agent, less than 10% (w/w) binder, 5-40% (w/w) filler, and less than    10% (w/w) lubricant and/or glidant.

Administration Regime

-   45. Use of a composition according to any one of the preceding    embodiments, wherein the composition is administered orally.

Functional Features

-   46. A composition according to any one of the preceding embodiments,    wherein said tablet has surface eroding properties.-   47. A composition according to any one of the preceding embodiments,    wherein said tablet has co-release of the GLP-1 agonist and the    delivery agent as determined by the concurrent release test    described herein.-   48. A composition according to any one of the preceding embodiments,    wherein said tablet has a disintegration time in the range of 7-15    minutes as determined by the disintegration test described herein.-   49. A composition according to any one of the preceding embodiments,    wherein said tablet has a hardness of at least 50 N as determined by    the hardness test described herein.

Use as a Medicament

-   50. Use of a composition as defined in any one of the preceding    embodiments in medicine.-   51. Use of a composition as defined in any one of the preceding    embodiments for treatment of type 2 diabetes or obesity.-   52. A method for the treatment of type 2 diabetes or obesity    comprising administering a composition as defined in any one of the    preceding embodiments.

EXAMPLES Example 1

The objective of the present study was to evaluate the oralbioavailability in beagle dogs of a series of compositions comprisingsemaglutide and SNAC.

Method Animals, Dosing and Blood Sampling

Twenty four male and 24 female beagle dogs, weighing 6-11 kg during thestudy period were included in the study. The dogs were dosed in fastingstate. The compositions were administered by a single oral dosing to thedogs in groups of 4 male and 4 females. Blood samples were taken at thefollowing time points: predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4,6, 8, 24, 48, 72, 96, 120, 144, 192 and 240 hours post dosing.

The i.v. solution (20 nmol/mL in a pH 7.4 solution comprising 0.1 mg/mlTween 20, 5.5 mg/ml Phenol, 1.42 mg/ml Na2HPO4 and 14 mg/ml PropyleneGlycol) was dosed in a dose volume of 0.1 mL/kg in the same dog colonyin one dosing group (n=8). Blood samples were taken at the followingtime points: predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 24,48, 72, 96, 120, 144, 192 and 240 hours post dosing.

Preparation of Plasma

All blood samples were collected into test tubes containing EDTA forstabilisation and kept on ice until centrifugation. Plasma was separatedfrom whole blood by centrifugation and the plasma was stored at −20° C.or lower until analysis.

Analysis of Plasma Samples

The plasma was analyzed for semaglutide using a Luminescence OxygenChanneling Immunoassay (LOCI). The LOCI assay employs donor beads coatedwith streptavidin and acceptor beads conjugated with a monoclonalantibody binding to a mid-molecular region of semaglutide. The othermonoclonal antibody, specific for an N-terminal epitope, wasbiotinylated. In the assay the three reactants were combined with thesemaglutide which form a two-sited immuno-complex. Illumination of thecomplex releases singlet oxygen atoms from the donor beads whichchannels into the acceptor beads and trigger chemiluminescence which wasmeasured in the EnVision plate reader. The amount of light wasproportional to the concentration of semaglutide and the lower limit ofquantification (LLOQ) in plasma was 100 pM.

Analysis of Compositions

The amount of semaglutide and SNAC in the composition were assayed usinga reversed-phase HPLC method, with UV detection at 230 nm, a lineargradient of mobile phases made up of deionised H2O:trifluoroacetic acid(TFA) (1000:1) (v/v) (A), and acetonitrile:TFA (1000:1) (v/v) (B).

Pharmacokinetic Calculations

Semaglutide plasma concentration data were subjected tonon-compartmental pharmacokinetic analysis using the PC based softwareWinNonlin, v. 5.2 (Pharsight, Mountain View, Calif. 94041, USA). Foreach individual dog the maximum plasma concentration (C_(max)) and timefor maximum plasma concentration (t_(max)) were read from the plasmaconcentration time curves. The following pharmacokinetic parameters wereestimated: Area Under the Curve to infinity (AUCinf.), and AUCinf./Dose(AUCinf./D). Bioavailability (F) was calculated as the fraction absorbed(in %) based on the dose normalised AUC (AUCinf./D) following oral andintravenous administration. Summary statistics of pharmacokineticresults were presented as arithmetic mean with calculated standarddeviation, also for T_(max) and plasma half life.

Preparation of Compositions

Tablets with different amounts of SNAC (150, 300 and 600 mg) andsemaglutide (5, 10, 15 and 20 mg) were prepared. The composition of thetablets is shown in Table 1.

TABLE 1 Tablet composition expressed as “per tablet” Composition A B C DE F Semaglutide (mg) 10 10 10 5 15 20 SNAC (mg) 150 300 600 300 300 300Povidone (mg) 2 4 7 3.5 4 4 Extragranular Avicel PH 102 (mg) 36 82 76 3877 72 Magesium Stearate 2 4 7 3.5 4 4 (mg) Tablet Weight (mg) 200 400700 350 400 400

Semaglutide was prepared according to the method described inWO2006/097537, Example 4, and subsequently freeze-dried. SNAC wasprepared according to the method described in WO2008/028859. Thecompositions were prepared using the following manufacturing process:

1) The ingredients were first screened through a #35 mesh;2) semaglutide and SNAC were geometrically blended in a mortar andpestle;3) povidone was dissolved in water and the resulting solution was usedto granulate the blend of semaglutide and SNAC;4) the granules were dried at a temperature not exceeding 40° C. to amoisture level of 4%; and5) the resulting dried granules were milled through a #35 mesh;6) finally, the granules were blended with the extra granularingredients (see Table 1) and the final blend was compressed intotablets, wherein the compression was performed at a pressure ofapproximately 4.4 kN or higher.

The tablet hardness of was more than 50 N as determined by the PharmaTest (33AA02), which measures the force required to disrupt the tablet,and the test is based on the pharmacopeia method Ph Eur 2.9.8.

Results

Table 2 summarises the pharmacokinetic parameters for semaglutide fromsingle dosing of the tablets shown in Table 1.

TABLE 2 Summary of pharmacokinetic parameters for semaglutide fromsingle dosing of tablets comprising 10 mg semaglutide in combinationwith 150 mg (A), 300 mg (B) or 600 mg (C) SNAC. SNAC T_(max) C_(max) FComposition (mg) (h) (pM) AUCinf./D (%) A 150 0.6 6222 0.62 0.17 B 3000.8 21871 2.335 0.63 C 600 1.1 9972 1.09 0.29

Individual and mean (SD) calculated pharmacokinetic parameters followingoral dosing appear from Tables 3 to 5 and following intravenousadministration appear from Table 6.

TABLE 3 Pharmacokinetic parameters for semaglutide following oral dosingof oral dosing of the combination of 10 mg semaglutide and 150 mg SNAC(Composition A) to 4 male and 4 female Beagle dogs. AUCinf./D DoseT_(max) C_(max) (h*kg*pmol/ F Dog no (nmol/kg) (h) (pM) l/pmol) (%) 1025285 1.5 38300 4.08 1.1 1026 548 n.a. 0 0 0 1027 278 0.2 228 0 0.000031028 338 2.0 3410 0.31 0.08 1029 246 n.a. 0 0 0 1030 244 0.2 2030 0.070.02 1031 223 n.a. 0 0 0 1032 254 0.5 5810 0.47 0.13 Mean 302 0.6 62220.62 0.17 SD 105 0.5 13130 1.41 0.38 n.a.) not analysed

TABLE 4 Pharmacokinetic parameters for semaglutide following oral dosingof oral dosing of the combination of 10 mg semaglutide and 300 mg SNAC(Composition B) to 4 male and 4 female Beagle dogs. AUCinf./D DoseT_(max) C_(max) (h*kg*pmol/ F Dog no (nmol/kg) (h) (pM) l/pmol) (%) 1033294 0.5 5540 0.35 0.09 1034 301 2.0 72000 6.83 1.8 1035 276 n.a. 0 0 01036 258 1.5 21100 2.52 0.68 1037 239 2.0 70000 8.73 2.3 1038 261 0.74050 0.28 0.07 1039 223 0.5 2010 0.07 0.02 1040 249 0.2 271 0.00 0.0001Mean 263 0.8 21871 2.35 0.63 SD 26.7 0.5 31061 3.49 0.94 n.a.) notanalysed

TABLE 5 Pharmacokinetic parameters for semaglutide following oral dosingof the combination of 10 mg semaglutide and 600 mg SNAC (Composition C)to 4 male and 4 female Beagle dogs. AUCinf./D Dose T_(max) C_(max)(h*kg*pmol/ F Dog no (nmol/kg) (h) (pM) l/pmol) (%) 1041 262 n.a. 0 0 01042 278 0.5 1890 0.52 0.14 1043 265 3.0 261 0 0.0005 1044 265 0.7 12700.02 0.01 1045 251 1.5 48400 5.2 1.4 1046 285 2.0 22900 2.53 0.68 1047226 0.7 4100 0.4 0.11 1048 248 0.7 953 0.01 0.004 Mean 260 1.1 9972 1.090.29 SD 18 0.5 17298 1.87 0.50 n.a.) not analysed

TABLE 6 Pharmacokinetic parameters for semaglutide following intravenousdosing of 2 nmol/kg semaglutide to 4 male and 4 female Beagle dogs.AUCinf./D Dose T_(max) C_(max) (h*kg*pmol/ Dog no (pmol/kg) (h) (pM)l/pmol) 1065 1980 0.5 31400 310 1066 1980 0.2 17400 227 1067 1980 0.228300 385 1068 1980 4.0 12900 384 1069 1980 0.2 28300 398 1070 1980 0.227400 383 1071 1980 0.2 31000 472 1072 1980 0.2 25700 418 Mean 1980 0.825300 372 SD 0 1.3 6638 73.8

TABLE 7 Summary of pharmacokinetic parameters for semaglutide fromsingle dosing of composition comprising 300 mg SNAC in combination with5, 10, 15 or 20 mg semaglutide. SNAC Semaglutide T_(max) C_(max) FComposition (mg) (mg) (h) (pM) AUCinf./D (%) D 300  5 0.5 4446 1.22 0.33B 300 10 0.8 21871 2.33 0.63 E 300 15 1.0 42612 4.61 1.2 F 300 20 1.39603 5.09 1.4

TABLE 8 Pharmacokinetic parameters for semaglutide following oral dosingof the combination of 5 mg semaglutide and 300 mg SNAC (Composition D)to 4 male and 4 female Beagle dogs. AUCinf./D Dose T_(max) C_(max)(h*kg*pmol/ F Dog no (nmol/kg) (h) (pM) l/pmol) (%) 1049 123 1 4490 1.540.41 1050 153 0.7 4420 0.5 0.13 1051 114 1 17200 4.27 1.1 1052 131 0.22390 0.52 0.14 1053 119 0.5 1860 0.31 0.08 1054 131 0.2 575 0.03 0.011055 113 0.7 3210 0.45 0.12 1056 107 0.5 1420 2.16 0.58 Mean 124 0.54446 1.22 0.33 SD 15 0.5 5335 1.42 0.38

TABLE 9 Pharmacokinetic parameters for semaglutide following oral dosingof the combination of 15 mg semaglutide and 300 mg SNAC (Composition E)to 6 Beagle dogs. AUCinf./D Dose T_(max) C_(max) (h*kg*pmol/ F Dog no(nmol/kg) (h) (pM) l/pmol) (%) 1067 318 1 56500 5.18 1.4 1068 393 1.561000 4.75 1.3 1069 322 1 15100 1.23 0.3 1070 341 0.5 2090 0 0.01 1071283 2.5 114000 16.00 4.3 1072 312 0.5 6980 0.47 0.1 Mean 328 1.0 426124.61 1.2 SD 37 0.8 43118 6.00 1.6

TABLE 10 Pharmacokinetic parameters for semaglutide following oraldosing of the combination of 20 mg semaglutide and 300 mg SNAC(Composition F) to 4 male and 4 female Beagle dogs. AUCinf./D DoseT_(max) C_(max) (h*kg*pmol/ F Dog no (nmol/kg) (h) (pM) l/pmol) (%) 1057588 1 197000 9.60 2.6 1058 619 1.5 144000 7.11 1.9 1059 508 1.5 774004.45 1.2 1060 519 1.5 91900 5.18 1.4 1061 519 2 70400 4.72 1.3 1062 5191.5 155000 9.09 2.4 1063 460 0.7 1620 0.01 0.004 1064 487 1.5 11500 0.610.16 Mean 527 1.3 93603 5.09 1.4 SD 52 0.5 68667 3.52 0.95

CONCLUSION

Surprisingly, tablets comprising 300 mg SNAC showed improvedbioavailability in the current study compared to tablets comprising 150mg or 600 mg SNAC.

1. A solid composition for oral administration comprising a GLP-1agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid,wherein the amount of said salt of N(8-(2-hydroxybenzoyl)amino)caprylicacid is at least 0.6 or at least 0.8 mmol; and said GLP-1 agonistoptionally comprises one substituent.
 2. A composition according toclaim 1, wherein said composition is in the form of a tablet.
 3. Acomposition according to claim 1, wherein said salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid is sodiumN-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC).
 4. A compositionaccording to claim 1, wherein the amount of said salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid is in the range of 0.6-2.1mmol, such as 0.6-1.9 mmol, 0.7-1.7 mmol or 0.8-1.3 mmol.
 5. Acomposition according to claim 1, wherein the amount of said salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid is up to 2.1 mmol, such asselected from the group consisting of up to 2.1 mmol, up to 2 mmol, upto 1.9 mmol, up to 1.8 mmol, up to 1.7 mmol, up to 1.6 mmol, up to 1.5mmol, up to 1.4 mmol, up to 1.3 mmol, up to 1.2 mmol and up to 1.1 mmol.6. A composition according to claim 1, wherein the amount of the GLP-1agonist is in the range of 0.01 mg to 100 mg.
 7. A composition accordingto claim 1, wherein said GLP-1 agonist is GLP-1 (7-37), GLP-1(7-36)amide, exendin-4 or an analogue thereof comprising up to 10substitutions, deletions, additions and/or insertions, and wherein saidGLP-1 agonist optionally comprises one substituent.
 8. A compositionaccording to claim 7, wherein said substituent comprises a fatty acid ora fatty diacid.
 9. A composition according to claim 8, wherein saidsubstituent comprises formula (X)

wherein n is at least 13, such as n is 13, 14, 15, 16, 17, 18 or
 19. 10.A composition according to claim 1, wherein the amount of GLP-1 is inthe range of 0.05 to 25 μmol, such as in the range of 0.5 to 2.5 μmol.11. A composition according to claim 1, wherein said compositioncomprises at least one additional pharmaceutically acceptable excipient.